Process for making 2-amino-4-hydroxyquinolines

ABSTRACT

The reaction of isatoic anhydrides with malononitrile in a reaction-inert solvent in the presence of a base to produce 2-amino-3-cyano-4-hydroxy-quinolines and 2-amino-α,α-dicyanoacetophenones which are then hydrolyzed and decarboxylated under acid or base conditions to produce 2-amino-4-hydroxy-quinolines, useful as intermediates for preparation of 1-oxo-1H-6-alkoxy-pyrimido[1,2-a]quinoline-2-carboxylic acids and esters of value as antiallergy agents.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of U.S. application Ser. No. 890,738,filed Mar. 27, 1978, and a continuation-in-part of U.S. application Ser.No. 759,295, filed Jan. 14, 1977 and now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a process for production of2-amino-4-hydroxy-quinolines and to intermediates therefor. Moreparticularly, it relates to the reaction of an isatoic anhydride withmalononitrile in the presence of a base to produce as intermediate a2-amino-α,α-dicyanoacetophenone and a2-amino-3-cyano-4-hydroxyquinoline, followed by hydrolysis anddecarboxylation of said intermediates under acid or base conditions.

2. Description of the Prior Art

The synthesis of 2-amino-4-hydroxyquinolines via the fusion of ethylcyanoacetate with anilinium benzenesulfonate or p-toluenesulfonate isdescribed by Hardman et al., J. Chem. Soc., 3878 (1954). Gabriel, Ber.,51, 1500 (1918) reports preparation of 2-amino-4-hydroxyquinoline byreduction of ethyl α-cyano-α-(o-nitrobenzoyl)acetate and by hydrolysisof α-cyano-α-(o-phthalimidobenzoyl)acetate. These methods, however, arecharacterized by relatively low yields, poor availability of necessaryreactants and, in the case of the fusion procedure described above,limitation as to the amount of product which can be made in a singlepreparation.

For convenience, isatoic anhydride, the trivial but widely used andrecognized name for 2H-3,1-benzoxazine-2,4(1H)-dione, is used throughoutthis document.

The reaction of N-alkyl isatoic anhydrides with malonic acid esters toproduce N-alkylquinolinediones is reported by Coppola, et al, J. Org.Chem., 41, 825 (1976). The replacement of malonic esters by compoundshaving an active methylene group and an electrophilic group capable ofreacting with the liberated anilino nitrogen, for example, carbanions ofthe appropriate nitroacetate, phosphonoacetate, phosphonoacetonitrile orβ-ketosulfone, permits introduction of nitrogen, phosphorous or sulfursubstituents in the 3-position of the quinoline system.

Coppola, et al, (loc. cit.), also describe the reaction ofN-(3-chloropropyl)isatoic anhydride and of N-(2-propynyl)isatoicanhydride with the sodium salt of malononitrile to produce2,3,4,6-tetrahydro-6-oxo-1H-pyrimido[1,2-a]quinoline-5-carbonitrile and1,2,3,5-tetrahydro-2-methylene-5-oxoimidazo[1,2-a]quinoline-4-carbonitrile,respectively.

SUMMARY OF THE INVENTION

It has now been found that 2-amino-4-hydroxyquinolines can beconveniently prepared by a process which comprises the steps of (a)reacting an isatoic anhydride with malononitrile in a reaction-inertsolvent under basic conditions and (b) then treating the reactionproduct of step (a) thus produced with acid or base.

The process is of general applicability to the synthesis of2-amino-4-hydroxyquinolines. Particular interest, however, resides inthe 2-amino-4-hydroxyquinolines having the formula ##STR1## and acidaddition salts thereof, wherein each of R₁, R₂ and R₃ is selected fromthe group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms,alkoxy having from 1 to 5 carbon atoms, fluoro, chloro, bromo,methylthio and methylsulfinyl; with the proviso that no more than two ofR₁, R₂ and R₃ are bulky groups; i.e., branched chain alkyl or branchedchain alkoxy, and when two of said R₁, R₂ and R₃ are bulky groups theyare located on non-adjacent positions;

R₂ and R₃ when taken together are selected from the group consisting of1,3-butadienyl and alkylenedioxy of 1 to 2 carbon atoms;

because of their use as intermediates for production of1-oxo-1H-6-alkoxypyrimido[1,2-a]quinoline-2-carboxylic acids and esterswhich are of value as antiallergy agents. These latter compounds, theirpreparation and use are described in Belgian Pat. No. 827,407, grantedOct. 1, 1975.

DETAILED DESCRIPTION OF THE INVENTION

Step (a) of the process of this invention, the reaction of an isatoicanhydride with malononitrile, is conducted in a reaction-inert solventin the presence of a base.

Suitable solvents for this step are the following and mixtures thereof;N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,2,4-dimethyltetrahydrothiophene 1,1-dioxide, hexamethylphosphoramide,cyclic and acyclic ethers, alkanols especially those having up to tencarbon atoms, crown ethers (macrocyclic polyethers) such as thosedescribed by Pedersen in J. Am. Chem. Soc., 89, 7017 (1967) and byPedersen et al in Angew. Chem. Internat. Edit. 11, 16 (1972), andaromatic hydrocarbons such as benzene, xylene and toluene.

As illustrated herein, not all the reactants need be soluble in theparticular solvent used. It is sufficient if either the isatoicanhydride reactant or the malononitrile be soluble in the solvent used,and that the reactants and products not enter into reaction with thesolvent, except as noted below, under the reaction conditions used. Theexception refers to possible reaction of the base with the solvent.

Bases suitable for the reaction of step (a) comprise a wide variety ofbases of organic and inorganic nature which can be used. Representativeorganic bases are trialkylamines, especially those having from three totwelve carbon atoms; N-methylmorpholine and N,N-dimethylaniline.Representative inorganic bases are alkali metal amides, alkoxides,hydrides and hydroxides, especially those of sodium and potassium;triphenylmethyl sodium; and metallic sodium and potassium.

As the man skilled in the art will recognize, some of the useful basesenumerated above, particularly those of inorganic nature, will reactwith certain solvents. Metallic sodium or potassium, for example, willreact with alkanols; and alkali metal hydroxides will react with crownethers. Thus, depending upon the extent of its reaction with thesolvent, the base added to the reaction may or may not be the base whichactually expedites the reaction. However, included within the basessuitable for the reaction of step (a) are those formed by reaction ofthe added base with the solvent.

The reaction of step (a) is conducted at a temperature of from about 20°C. to about 150° C. The favored temperature is from about 50° C. toabout 100° C. and the preferred range from about 50° C. to about 60° C.

The products of the reaction of step (a) are2-amino-α,α-dicyano-acetophenones (formula III) and2-amino-3-cyano-4-hydroxyquinolines (formula IV). It appears thatformula III compounds are produced first and, under the conditions ofthe reaction, undergo partial cyclization to formula IV compounds,particularly if the reaction mixture is heated above 80° C. or is heatedat 50°-60° C. for prolonged periods of time. ##STR2##

The formation of a mixture of compounds of formulae III and IV in step(a) is immaterial to the overall process of this invention since, underthe conditions of step (b), they are each converted to4-hydroxyquinolines (formula I). Separation of the compounds is notnecessary. For reasons of convenience and economy, it is preferred touse the reaction product of step (a) without purification in step (b).They are recovered by acidifying the reaction mixture, for example bypouring the reaction mixture into cold dilute hydrochloric acid. Theresulting precipitate, a mixture of the above-named products, is thentreated with acid or base, step (b), to produce the desired2-amino-4-hydroxyquinolines.

In step (b), the reaction product of step (a) is treated with a strongacid or a strong base at a temperature ranging from about 80° C. toabout 150° C. Higher temperatures appear to offer no advantage and mayeven reduce the yield of the desired product as a result of degradationreactions. At lower temperatures the reaction is so slow as to be of nopractical use.

The choice of acid or base conditions to convert the reaction product ofstep (a) to the desired 2-amino-4-hydroxyquinoline is dependent upon thevalue of the R₁, R₂ and R₃ substituents. When R₁, R₂ or R₃ is a groupwhich would undergo reaction with acid, e.g., an ether group, andretention of said group in its original form is desired, then a base isused in step (b) to achieve the aforesaid conversion. If hydrolysis ofthe ether group is desired, then, of course, an acid, e.g. HBr, can beused to accomplish the conversion of the step (a) reaction product to a2-amino-4-hydroxyquinoline and hydrolysis of the ether group in a singlestep.

The isolated reaction product of step (a) is suspended in a strong acidor strong base and the resulting mixture heated to a temperature of fromabout 80° C. to about 125° C. Suitable strong acids are hydrobromicacid, hydrobromic acid-acetic acid, sulfuric acid and hydrochloric acid.When using hydrochloric acid, the reaction is carried out under pressureas, for example, in a glass bomb. The favored acid is hydrobromic acid,especially 48% hydrobromic acid, since it affords good yields of thedesired 2-amino-4-hydroxyquinolines in a readily isolable form, i.e., asthe hydrobromide salts.

The products resulting from acid treatment of step (a) reaction productsare isolated in the form of their acid addition salts corresponding tothe acid used by chilling the reaction mixture, or by evaporation. Theyare converted to their base form by neutralization of an aqueoussolution (or suspension) of the acid with base. The2-amino-4-hydroxyquinoline products generally precipitate and arerecovered by filtration. If precipitation of the2-amino-4-hydroxyquinoline product does not occur, it is recovered byevaporation or by addition of a water-miscible organic solvent toprecipitate it from the solution.

As noted above, conversion of the reaction product of step (a) to a2-amino-4-hydroxyquinoline can also be accomplished by treatment with astrong base. Suitable strong bases are the alkali metal hydroxides,especially aqueous solutions of sodium or potassium hydroxide of 6 N orhigher concentration, since they afford satisfactory yields of desired2-amino-4-hydroxy-quinolines. The products are recovered byneutralization of the alkaline reaction mixture to precipitate the free2-amino-4-hydroxyquinoline.

Many of the required isatoic anhydride reactants are availablecommercially. Those which are not are conveniently synthesized from theappropriate anthranilic acid and phosgene according to the procedurereported by Wagner et al., Org. Sync., Coll. Vol. III, 488 (1955). Therequisite anthranilic acids, if not known compounds, are readilyobtainable from appropriately substituted phthalic anhydrides by methodsknown to those skilled in the art. A typical procedure would, forexample begin with the appropriate phthalic anhydride which is convertedto phthalimide by reaction with ammonia followed by reaction of thethus-produced phthalimide with sodium hypochlorite in alkaline solutionat a temperature of 75°-85° C. (see Fieser and Fieser, "OrganicChemistry", D. C. Heath and Company, Boston, Mass., 1944, p. 671).

The 2-amino-4-hydroxyquinolines are valuable intermediates forproduction of 1-oxo-1H-6-alkoxypyrimido[1,2-a]quinoline-2-carboxylicacids and its esters which are useful as antiallergy agents and have theformula ##STR3## wherein R₁, R₂ and R₃ are as defined above; R₄ ishydrogen or alkyl; and R₅ is alkoxy having from 1 to 5 carbon atoms.

Compounds of formula II are prepared from 2-amino-4-hydroxyquinolines bythe reaction sequence comprising conversion of the appropriate2-amino-4-hydroxyquinoline to a 2-amino-4-alkoxyquinoline by reactionwith a lower alkyl ester of an arylsulfonic acid or by reaction, astheir sodium salts, with a lower alkyl halide. The thus-produced2-amino-4-alkoxyquinolines are then condensed with a dialkylethoxymethylenemalonate in a reaction-inert solvent at from 80° C. to125° C., to give a dialkyl 4-alkoxy-2-quinolylaminomethylene-malonatewhich is then cyclized by heating from 175° C. to 250° C. in areaction-inert solvent such as a mixture of diphenyl ether and diphenyl,especially that which contains 26.5% diphenyl and 73.5% diphenyl etherand is sold under the trademark Dowtherm A (Dow Chemical Co., Midland,Mich.).

The thus-produced alkyl1-oxo-1H-6-alkoxypyrimido[1,2-a]quinoline-2-carboxylates are thenhydrolyzed to the corresponding acids, for example, by heating anaqueous mixture of the appropriate ester with hydrochloric acid at fromabout 50° C. to 100° C. until hydrolysis is complete. The acids arerecovered by filtration if they precipitate upon cooling the reactionmixture, or by evaporation of the reaction mixture.

They can be administered either as individual therapeutic agents or asmixtures of therapeutic agents; for example, with theophylline orsympathomimetic amines, with or without a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice. For example, they can be combined with variouspharmaceutically-acceptable inert carriers in the form of tablets,capsules, aerosol sprays, aqueous suspensions or solutions, injectablesolutions, elixirs, syrups and the like.

For the purpose of parenteral administration and inhalation, solutionsor suspensions of these compounds in sesame or peanut oil or in aqueouspropylene glycol solutions can be employed. These particular solutionsare especially suited for intramuscular and subcutaneous injectionpurposes should such method of administration be desired. The aqueoussolutions are also useful for intravenous injection purposes providedthat their pH is properly adjusted beforehand.

The compounds can be administered to asthmatic subjects suffering frombronchoconstriction by means of inhalators or other devices which permitthe active compounds to come into direct contact with the constrictedareas of the tissues of the subject.

The dosage regimen of said compounds will, of course, vary with age,weight and response of the particular patient as well as with the natureand extent of the symptoms, the pharmacodynamic characteristics of theparticular agent to be administered and the route of administrationchosen.

An effective daily oral dosage of said compounds in humans of from about10 to about 1500 mg. per day, with a preferred range of about 10 toabout 600 mg. per day in single or divided doses, or at about 0.2 toabout 12 mg./kg. of body weight will effectively alleviatebronchoconstriction in human subjects.

When administered intravenously or by inhalation, the effective dailydose is from about 0.5 to about 400 mg. per day, and preferably fromabout 0.25 to 200 mg. per day, or at about 0.005 to 4 mg./kg. of bodyweight in single or divided doses.

The antiallergy property of the1-oxo-1H-6-alkoxypyrimido[1,2-a]quinoline-2-carboxylic acids and estersis evaluated by the passive cutaneous anaphylaxis (PCA) test (Ovary, J.Immun., 81, 355, 1958). In the PCA test, normal animals are injectedintradermally (i.d.) with antibodies contained in serum obtained fromactively sensitized animals. The animals are then challengedintravenously with antigen mixed with a dye such as Evans' Blue. Theincreased capillary permeability caused by the antigen-antibody reactioncauses the dye to leak from the site of the antibody injection. The testanimals are then asphyxiated and the intensity of the reactiondetermined by measuring the diameter and intensity of the bluecoloration on the inner surface of the animals' skin.

EXAMPLE 1 2-Amino-4-hydroxyquinoline

A solution of isatoic anhydride (49.8 g., 0.3 mole) in 300 ml. ofN,N-dimethylformamide is added, during 30 minutes, to a warm (50°-60°C.) solution of malononitrile (21.8 g., 0.33 mole) and triethylamine(33.4 g., 0.33 mole) in 100 ml. of N,N-dimethylformamide. Briskevolution of carbon dioxide is observed. The reaction mixture ismaintained at 50°-60° C. for 30 minutes after addition of the anhydrideis completed and is then poured into 2500 ml. of ice-cold 0.2 Nhydrochloric acid. The precipitate which forms is isolated by filtrationand dried. It is then suspended in 48% hydrobromic acid (1500 ml.) andthe mixture refluxed for 20 hours. The resulting clear solution ischilled in an ice bath and the precipitate which forms collected byfiltration. It is then dissolved in warm water and, after filtering toremove a small amount of insoluble material, the solution is madealkaline with ammonium hydroxide. The resulting precipitate is filtered,washed with water and isopropanol, and dried to give 41.2 g. (86%) ofproduct; m.p. 298°-300° C., dec. An analytical sample is recrystallizedfrom methanol-water, m.p. 300° C., dec.

Analysis: Calc'd for C₉ H₈ N₂ O: C, 67.47; H, 5.03; N, 17.49%. Found: C,67.23; H, 5.12; N, 17.50%.

MS: m/e=160 (m⁺).

Repetition of this reaction but replacing triethylamine withN-methyl-morpholine, N,N-dimethylaniline, tri-n-butylamine, N-decyldimethylamine, N-hexyl dimethylamine, sodamide, triphenylmethyl sodium,sodium hydride, potassium ethoxide, metallic sodium, or potassiumhydroxide, affords the same product.

EXAMPLE 2 2-Amino-4-hydroxy-6-methylquinoline

A solution of 5-methyl isatoic anhydride (19.5 g., 0.11 mole) in 150 ml.of N,N-dimethylformamide is added, during 15 minutes, to a warm (55°-60°C.) solution of malononitrile (7.9 g., 0.12 mole) and triethylamine(12.1 g., 0.12 mole) in N,N-dimethylformamide (100 ml.). Carbon dioxideis evolved and the reaction mixture is stirred for 30 minutes afteraddition of the anhydride is complete without further heating. Theresulting clear, dark solution is poured into ice-cold 0.2 Nhydrochloric acid (1220 ml.). The solid which separates is isolated byfiltration and dried (19.5 g.). A portion of said solid (9.5 g.) is thensuspended in 48% hydrobromic acid (250 ml.)-acetic acid (50 ml.) and themixture refluxed for 20 hours. The clear solution that results ischilled in an ice bath and the precipitate which forms is collected byfiltration. It is dissolved in ethanol-water (200 ml. of 1:1) and, afterfiltering to remove a small amount of insoluble material, the filtratemade alkaline with ammonium hydroxide. Crushed ice is added and thesolid which precipitates is filtered and dried: 6.2 g. (73%); m.p. 343°C. (dec.).

An analytical sample is prepared by recrystallization frommethanol-water.

Analysis: Calc'd for C₁₀ H₁₀ N₂ O: C, 68.94; H, 5.79; N, 16.08%. Found:C, 68.75; H, 5.84; N, 16.06%.

EXAMPLE 3 2-Amino-6-chloro-4-hydroxyquinoline

Following the procedure of Example 2, 5-chloroisatoic anhydride (19.8g., 0.1 mole), malononitrile (7.3 g., 0.11 mole) and triethylamine (11.1g., 0.11 mole) are reacted together in N,N-dimethylformamide (200 ml.)to give 20 g. of product. Five grams of said product are refluxed for 22hours in 48% hydrobromic acid (175 ml.) to give 4.2 g. (86%) yield oftitle product; m.p. 356° C. (dec.).

Analysis: Calc'd for C₉ H₇ ClN₂ O: C, 55.54; H, 3.63; N, 14.40%. Found:C, 55.17; H, 3.68; N, 14.26%.

Repetition of this procedure but using 12 N sulfuric acid in place ofhydrobromic acid affords the same product.

EXAMPLE 4 2-Amino-6-methoxy-4-hydroxyquinoline

To a solution of malononitrile (6.0 g., 0.91 mole) and triethylamine(9.2 g., 0.091 mole) in N,N-dimethylformamide (50 ml.) at 55°-60° C. isadded rapidly, and with stirring, a solution of 5-methoxy isatoicanhydride in N,N-dimethylformamide (100 ml.). The reaction mixture ismaintained at 55°-60° C. during addition. Carbon dioxide is evolved andthe reaction mixture is stirred for a half-hour following completion ofaddition without application of further heating. The clear solution ispoured into 0.2 N of cold hydrochloric acid (1015 ml.) and the resultingprecipitate separated by filtration and dried: 16.5 g.; m.p. >370° C.

A portion of said product (1.08 g.) is added to 6 N potassium hydroxidesolution (20 ml.) and the mixture heated to reflux for about 18 hours.The clear, dark solution formed is cooled and acidified with aceticacid. The dark brown solid which precipitates is filtered, taken up inethanol-water (1:2, 30 ml.) and the solution made alkaline with ammoniumhydroxide. The resulting solid is filtered and dried. Yield=710 mg.(69%); m.p. 298°-300° C.

MS: m/e=190 (m⁺).

Analysis: Calc'd for C₁₀ H₁₀ N₂ O₂ : C, 63.14; H, 5.30; N, 14.73%.Found: C, 62.85; H, 5.23; N, 14.56%.

EXAMPLE 5 2-Amino-α,α-Dicyanoacetophenone

To a solution of malononitrile (7.3 g., 0.11 mole) inN,N-dimethylformamide (150 ml.) is added sodium hydride (4.7 g., 0.11mole) Carbon dioxide is evolved and the mixture is stirred for tenminutes. Isatoic anhydride (16.3 g., 0.10 mole) is added to the reactionmixture which is then heated to 50°-60° C. for 30 minutes. The reactionmixture is then cooled and poured into cold water (1000 ml.). Theaqueous mixture is filtered to remove a small amount of amorphousprecipitate. The filtrate is made strongly acid with concentratedhydrochloric acid and the resulting precipitate separated by filtration,washed with water and dried (18.0 g.) M.P.=>300° C. Infrared analysis(Nujol) of the product showed complete absence of carbonyl absorptionand a strong C.tbd.N peak at 4.5μ. The product gives a positive ferricchloride test.

EXAMPLE 6 2-Amino-3-cyano-4-hydroxyquinoline

The product of Example 5 is recrystallized from N,N-dimethylformamide togive a colorless crystalline product; M.P. >360° C. Infrared analysis inNujol shows carbonyl absorption at 6μ and C.tbd.N absorption at 4.5μ.The product gives a negative chloride test.

Analysis: Calc'd for C₁₀ H₇ N₃ O: C, 64.86; H, 3.81; N, 22.69%. Found:C, 64.69; H, 4.00; N, 22.55%.

EXAMPLE 7 2-Amino-4-hydroxyquinoline

The product of Example 5 is suspended in 48% hydrobromic acid (30 ml.per gram) and the mixture refluxed for 20 hours. The resulting clearsolution is chilled in an ice bath and the precipitate which formscollected by filtration. It is dissolved in warm water, the solutionfiltered and the filtrate made alkaline with ammonium hydroxide. Theprecipitate which forms is filtered, washed with water and isopropanol,and air dried. The product is identical to that of Example 1.

EXAMPLE 8

The procedures of Examples 1 and 4 are repeated but using theappropriate isatoic anhydride as reactant to give the followingcompounds. When any of R₁, R₂ or R₃ is alkoxy, the procedure of Example4 is used.

    ______________________________________                                         ##STR4##                                                                      R.sub.1     R.sub.2       R.sub.3                                            ______________________________________                                        7-OCH.sub.3 H             H                                                   6-OCH.sub.3 7-OCH.sub.3   H                                                   6-OC.sub.2 H.sub.5                                                                        H             H                                                   6-F         H             H                                                   H           7-F           H                                                   H           7-Cl          H                                                   6,7-CHCHCHCH          H                                                       5-CH.sub.3  H             8-OCH.sub.3                                         H           H             8-OCH.sub.3                                         H           H             8-Cl                                                6-CH.sub.3  H             8-CH.sub.3                                          6-i-C.sub.3 H.sub.7                                                                       H             H                                                   6,7-OCH.sub.2O        H                                                       H              7,8-OCH.sub.2O                                                 5-Br        H             H                                                   H           H             8-Br                                                H           6-n-C.sub.4 H.sub.9                                                                         H                                                   H           6-sec-C.sub.4 H.sub.9                                                                       H                                                   H           6-t-C.sub.4 H.sub.9                                                                         H                                                   5-Cl        H             H                                                   H           H             8-C.sub.2 H.sub.5                                   H           6-C.sub.2 H.sub.5                                                                           H                                                   H           6-OH          H                                                   H           H             7-OH                                                5-OH        H             H                                                   5-OCH.sub.3 H             8-OCH.sub.3                                         7-OC.sub.2 H.sub.5                                                                        H             8-OH                                                5-CH.sub.3  H             7-CH.sub.3                                          5,6-OCH.sub.2O        H                                                       6-O-i-C.sub.3 H.sub.7                                                                     7-O-i-C.sub.3 H.sub.7                                                                       H                                                   6-OH        H             8-OH                                                6-F         7-F           H                                                   6-OC.sub.2 H.sub.5                                                                        7-OC.sub.2 H.sub.5                                                                          H                                                   6-t-C.sub.4 H.sub.9                                                                       8-t-C.sub.4 H.sub.9                                                                         H                                                   H           7-Br          8-Br                                                H           7-Cl          8-OH                                                6,7-OCH.sub.2CH.sub.2O                                                                              H                                                       5-OCH.sub.3 H             7-OCH.sub.3                                         5-OC.sub.2 H.sub.5                                                                        H             8-OC.sub.2 H.sub.5                                  H           6-i-C.sub.3 H.sub.7                                                                         8-i-C.sub.3 H.sub.7                                 H           6-SCH.sub.3   H                                                   H           6-SOCH.sub.3  H                                                   H           H             7-SCH.sub.3                                         6-O-n-C.sub.4 H.sub.9                                                                     7-O-n-C.sub.4 H.sub.9                                                                       H                                                   H           6-O-n-C.sub.3 H.sub.7                                                                       7-Br                                                5-Cl        6-O-n-C.sub.3 H.sub.7                                                                       8-Cl                                                5-Br        6-SCH.sub.3   7-Br                                                H           H             7-n-C.sub.4 H.sub.9                                 5-Cl        6-O-n-C.sub.3 H.sub.7                                                                       7-Cl                                                H           6-SCH.sub.3   7-Cl                                                H           6-SOCH.sub.3  7-Cl                                                H           6-Cl          7-SCH.sub.3                                         H           6-Cl          7-SOCH.sub.3                                        H           6-SCH.sub.3   7-SOCH.sub.3                                        H           6-SCH.sub.3   7-SCH.sub.3                                         H           6-SOCH.sub.3  7-SOCH.sub.3                                        6-OCH.sub.3 7-OCH.sub.3   8-OCH.sub.3                                         5-OCH.sub.3 6-OCH.sub.3   7-OCH.sub.3                                         5-Cl        7-Cl          H                                                   6-Cl        7-Cl          H                                                   5-Cl        6-Br          H                                                   H              7,8-CHCHCHCH                                                   5-Br        7-Br          8-OH                                                5-Cl        7-Cl          8-OH                                                5-OH        6-CH.sub.3    8-OH                                                6-OCH.sub.3 7-OH          8-OCH.sub.3                                         6-CH.sub.3  7-CH.sub.3    8-OH                                                6-CH.sub.3  7-OH          8-CH.sub.3                                          H           H             8-O-n-C.sub.5 H.sub.11                              6-F         7-F           8-F                                                 H           5-SCH.sub.3   8-CH.sub.3                                          7-t-C.sub.5 H.sub.11                                                                      H             H                                                   7-CH.sub.3  8-CH.sub.3    5-i-C.sub.4 H.sub.9                                 5-OH        7-OCH.sub.3   8-CH.sub.3                                          ______________________________________                                    

EXAMPLE 9 2-Amino-4-hydroxyquinoline

The procedure of Example 1 is repeated on one-tenth the scale describedtherein and using concentrated hydrochloric acid in a sealed tube inplace of 48% hydrobromic acid. The hydrochloric acid treatment isconducted at 125° C. The product is identical to that of Example 1.

EXAMPLE 10

The procedure of Example 5 is repeated but using the appropriate isatoicanhydride to provide the following compounds:

    ______________________________________                                         ##STR5##                                                                      R.sub.1     R.sub.2       R.sub.3                                            ______________________________________                                        5-CH.sub. 3 H             H                                                   5-Cl        H             H                                                   5-OCH.sub.3 H             H                                                   6-OCH.sub.3 7-OCH.sub.3   H                                                   H           7-F           H                                                   H           H             8-Br                                                H           6-t-C.sub.4 H.sub.9                                                                         H                                                   3-Cl        H             H                                                   3-Br        5-Br          H                                                   3-OH        4-Cl          H                                                   4-CH.sub.3  5-CH.sub.3    H                                                   4-OC.sub.2 H.sub.5                                                                        5-OC.sub.2 H.sub.5                                                                          H                                                   5,6-OCH.sub.2CH.sub.2O                                                                              H                                                       6,7-OCH.sub.2O        H                                                       6,7-CHCHCHCH          H                                                       4-OCH.sub.3 5-OCH.sub.3   6-OCH.sub.3                                         H           6-SCH.sub.3   7-Cl                                                H           6-SOCH.sub.3  7-Cl                                                H           6-SOCH.sub.3  7-SOCH.sub.3                                        H           6-Cl          7-SCH.sub.3                                         5-Cl        7-Cl          H                                                   6-O-n-C.sub.4 H.sub.9                                                                     7-O-n-C.sub.4 H.sub.9                                                                       H                                                   H           6-i-C.sub.3 H.sub.7                                                                         8-i-C.sub.3 H.sub.7                                 4-t-C.sub.5 H.sub.11                                                                      H             H                                                   3-F         4-F           6-F                                                 3-CH.sub.3  4-OCH.sub.3   6-OH                                                3-CH.sub.3  4-OH          5-CH.sub.3                                          3-OH        4-CH.sub.3    6-CH.sub.3                                          3-OH        4-Cl          6-Cl                                                3-CH.sub.3  6-SCH.sub.3   H                                                   3-O-n-C.sub.5 H.sub.11                                                                    H             H                                                   3-CH.sub.3  4-CH.sub.3    6-i-C.sub.4 H.sub.9                                 ______________________________________                                    

EXAMPLE 11

Repetition of the procedure of Example 6 but using the appropriateisatoic anhydride affords the following compounds:

    ______________________________________                                         ##STR6##                                                                      R.sub.1     R.sub.2       R.sub.3                                            ______________________________________                                        5-CH.sub.3  H             H                                                   6-F         H             H                                                   H           7-F           H                                                   6-CH.sub.3  7-CH.sub.3    H                                                   H           6-n-C.sub.4 H.sub.9                                                                         H                                                   5-OH        H             H                                                   5-OCH.sub.3 H             8-OCH.sub.3                                         5-OCH.sub.3 6-OCH.sub.3   7-OCH.sub.3                                         6,7-CHCHCHCH          H                                                       H           7,8-OCH.sub.2O                                                    5-Cl        6-O-n-C.sub.3 H.sub.7                                                                       8-Cl                                                5-Br        6-SCH.sub.3   7-Br                                                H           6-SCH.sub.3   7-SCH.sub.3                                         H           6-SOCH.sub.3  7-SOCH.sub.3                                        7-OC.sub.2 H.sub.5                                                                        H             8-OH                                                5-OH        7-OCH.sub.3   8-CH.sub.3                                          5-CH.sub.3  7-CH.sub.3    8-OH                                                7-t-C.sub.5 H.sub.11                                                                      H             H                                                   7-CH.sub.3  8-CH.sub.3    5-i-C.sub.4 H.sub.9                                 6-F         7-F           8-F                                                 5-Cl        7-Cl          8-OH                                                ______________________________________                                    

EXAMPLE 12

The products of Examples 10 and 11 are hydrolyzed and decarboxylatedaccording to the procedure of Example 7 to provide compounds having theformula shown below wherein R₁, R₂, and R₃ are as defined in Examples 10and 11: ##STR7##

PREPARATION A Ethers of 2-Amino-4-hydroxyquinoline via Esters ofp-Toluenesulfonic Acid

A mixture of the appropriate 2-amino-4-hydroxyquinoline and theappropriate alkyl p-toluenesulfonate (10 to 20% molar excess) in xylene(from about 1-2 liters per mole of quinoline compound) is heated atreflux for 4-5 hours. It is then cooled, filtered and the filter cakewashed with xylene. The solid is slurried in 3 N KOH for 15-20 minutesand then filtered. The filter cake is washed with water, dried andrecrystallized from a suitable solvent.

via Alkylation with Alkyl Bromide

Equimolar amounts of the appropriate 2-amino-4-hydroxyquinoline andsodium hydride are reacted in warm N,N-dimethylformamide to produce thesodio derivative of the 2-amino-4-hydroxyquinoline. An equimolar amountof the alkyl bromide reactant is added and the reaction mixture heatedfor 20 minutes on a steam bath. It is then poured into water, the etherproduct separated by filtration or extracted with a suitable solventsuch as benzene or chloroform. The extract is dried (Na₂ SO₄) andevaporated. The products are crystallized from suitable solvents.

When any of R₁, R₂ or R₃ is hydroxy, sufficient quantities of sodiumhydride and the appropriate alkylbromide are used to convert all hydroxygroups to ether groups.

PREPARATION B Ethyl1-Oxo-1H-6-methoxypyrimido[1,2-a]quinoline-2-carboxylate

A. A mixture of 2-amino-4-methoxyquinoline (34 g., 0.196 mole) anddiethyl ethoxymethylenemalonate (46.8 g., 0.216 mole) is heated on asteam bath. A clear melt forms within about ten minutes and within abouttwenty minutes begins to resolidify. The mixture is heated a total of 45minutes and is then cooled. The product, diethyl4-methoxy-2-quinolylaminomethylenemalonate, is crystallized from ethanol(350 ml.) as a fluffy solid; m.p. 136.5°-137.5° C.

B. To Dowtherm A (350 ml.) at 100° C. is added the product from A (55 g,0.16 mole) and the resulting clear yellow solution heated to 230°-233°C. for 1.75 hours. The reaction mixture is cooled, diluted with ethylacetate (500 ml.) and then extracted with 1 N hydrochloric acid (3×120ml.). The extracts are combined, made basic with 20% ammonium hydroxideand chilled to precipitate the product. It is filtered andrecrystallized successively from ethanol, benzene-cyclohexane (1:1) andethanol to give 15.5 g. of the ethyl ester as yellow crystals; m.p.130°-130.5° C.

By means of the above preparations, the 2-amino-4-hydroxyquinolinesdescribed herein are converted to corresponding ethyl 1-oxo-1H-6-loweralkoxy-pyrimido[1,2-a]quinoline-2-carboxylates.

PREPARATION C 1-Oxo-1H-6-methoxypyrimido[1,2-a]quinoline-2-carboxylicAcid

A mixture of ethyl1-oxo-1H-6-methoxypyrimido[1,2-a]quinoline-2-carboxylate (3.0 g.) andconcentrated hydrochloric acid (60 ml.) is heated on a steam bath for ahalf hour. It is then cooled and filtered to give 0.87 g. of the titleproduct. It is recrystallized from N,N-dimethylformamide m.p. 219° C.(dec.).

In like manner, the products of Preparation B are hydrolyzed to thecorresponding acids.

What is claimed is:
 1. A process for production of2-amino-4-hydroxyquinolines having the formula ##STR8## wherein each ofR₁, R₂ and R₃ is selected from the group consisting of hydrogen, alkylhaving from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms,chloro, bromo, fluoro, hydroxy, methylthio and methylsulfinyl, and R₂and R₃ when taken together are selected from the group consisting of1,3-butadienyl and alkylenedioxy having from 1 to 2 carbon atoms; whichcomprises the steps of(a) reacting an isatoic anhydride of the formula##STR9## wherein R₁, R₂ and R₃ are as defined above, in a reaction-inertsolvent with malononitrile in the presence of a base selected from thegroup consisting of trialkylamines having from 3 to 12 carbon atoms,N,N-dimethylaniline, N-methylmorpholine, alkali metal amides, alkalimetal alkoxides, alkali metal hydrides, alkali metal hydroxides,triphenylmethyl sodium, sodium and potassium, at a temperature of fromabout 20° C. to about 150° C.; and (b) treating the reaction product ofstep (a) with (i) a strong acid selected from the group consisting ofhydrobromic acid, hydrobromic acid-acetic acid, hydrochloric acid andsulfuric acid, or (ii) a strong base selected from the group consistingof sodium hydroxide and potassium hydroxide at a temperature of fromabout 80° C. to about 150° C.
 2. A process according to claim 1 whereineach of R₁, R₂ and R₃ is hydrogen.
 3. A process according to claim 1wherein R₁ is alkoxy and each of R₂ and R₃ is hydrogen.
 4. A processaccording to claim 1 wherein R₁ is methyl and each of R₂ and R₃ ishydrogen.
 5. The process according to claim 2 wherein step (a) isconducted in the presence of triethylamine as base and the strong acidof step (b) is hydrobromic acid.
 6. The process according to claim 3wherein R₁ is 6-methoxy and triethylamine is used as base in step (a)and step (b) is conducted in the presence of the strong base potassiumhydroxide.